DESCRIPTION: Osteoporosis is a major skeletal pathology that not only reduces bone mass but also alters the properties of the constituent tissue. Antiresorptive drug therapies for osteoporosis moderately increase bone mass but substantially decrease fracture risk, suggesting that modified tissue properties may play a key role in fracture risk reduction in osteoporotic patients. The long-term objective of this application is to understand the relationship between bone fragility and disease- and treatment-induced changes in the structure and distribution of bone mineral and matrix. Accordingly, the following Specific Aims are proposed: To relate bone mineral and matrix properties, microarchitecture, and quantity to fracture incidence in (1) young, untreated bone tissue and (2) bone tissue treated with antiresorptive therapeutic agents. In Aim 1 iliac crest biopsies from young women of comparable BMD with and without fractures will be characterized with a) vibrational spectroscopy and backscattered electron imaging to assess mineral and matrix properties and b) microcomputed tomography (microCT) and histomorphometry to assess microarchitecture and bone volume fraction (BV/TV). Relationships among fracture incidence, BMD, mineral and matrix properties, and microarchitectural measures will be examined with a multiple logistic regression. In Aim 2 bisphosphonate-treated and age-matched control human biopsies will be characterized using the same methods described for Aim 1 to assess treatment-based differences in mineral and matrix parameters and microarchitectural measures. As before, the ability of these parameters to predict fracture will be assessed with a logistic regression. These studies will illuminate the relative contributions of mineral and matrix properties, microarchitecture, and bone quantity to fracture incidence in normal and osteoporotic tissue. In addition, they will provide crucial insights into the mechanisms by which osteoporosis increases bone fragility and by which bisphosphonates reduce fracture incidence in osteoporotic tissue. Relevance to Public Health: The goal of this study is to understand how changes in the molecular structure and spatial distribution of the mineral and protein in bone tissue affect the likelihood that it will fracture. Understanding the factors that contribute to skeletal fragility is essential for effective prevention and treatment of bone diseases like osteoporosis.